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Anti-Nuclear Antibody Production and Autoimmunity in Transgenic Mice That Overexpress the Transcription Factor Bright¹

Malini Shankar^*, Jamee C. Nixon^*, Shannon Maier, Jennifer Workman, A. Darise Farris^, and Carol F. Webb^2,*,,

^* Immunobiology and Cancer Program and Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Department of Microbiology and Immunobiology, and Cell Biology Department, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104

The B cell-restricted transcription factor, B cell regulator of Ig_H transcription (Bright), up-regulates Ig H chain transcription 3- to 7-fold in activated B cells in vitro. Bright function is dependent upon both active Bruton’s tyrosine kinase and its substrate, the transcription factor, TFII-I. In mouse and human B lymphocytes, Bright transcription is down-regulated in mature B cells, and its expression is tightly regulated during B cell differentiation. To determine how Bright expression affects B cell development, transgenic mice were generated that express Bright constitutively in all B lineage cells. These mice exhibited increases in total B220⁺ B lymphocyte lineage cells in the bone marrow, but the relative percentages of the individual subpopulations were not altered. Splenic immature transitional B cells were significantly expanded both in total cell numbers and as increased percentages of cells relative to other B cell subpopulations. Serum Ig levels, particularly IgG isotypes, were increased slightly in the Bright-transgenic mice compared with littermate controls. However, immunization studies suggest that responses to all foreign Ags were not increased globally. Moreover, 4-wk-old Bright-transgenic mice produced anti-nuclear Abs. Older animals developed Ab deposits in the kidney glomeruli, but did not succumb to further autoimmune sequelae. These data indicate that enhanced Bright expression results in failure to maintain B cell tolerance and suggest a previously unappreciated role for Bright regulation in immature B cells. Bright is the first B cell-restricted transcription factor demonstrated to induce autoimmunity. Therefore, the Bright transgenics provide a novel model system for future analyses of B cell autoreactivity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant AI044215 (to C.F.W.).

² Address correspondence and reprint requests to Dr. Carol F. Webb, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104. E-mail address: carol-webb{at}omrf.ouhsc.edu

³ Abbreviations used in this paper: ANA, anti-nuclear Ab; Bright, B cell regulator of Ig_H transcription; Btk, Bruton’s tyrosine kinase; PC, phosphorylcholine; KLH, keyhole limpet hemocyanin; DAPI, 4', 6-diamidino-2-phenylindole; DN, dominant negative; NP, nitrophenyl.

This article has been cited by other articles:

				J. C. Nixon, S. Ferrell, C. Miner, A. L. Oldham, U. Hochgeschwender, and C. F. Webb Transgenic Mice Expressing Dominant-Negative Bright Exhibit Defects in B1 B Cells J. Immunol., November 15, 2008; 181(10): 6913 - 6922. [Abstract] [Full Text] [PDF]